Characteristics of adults with potential refractory chronic cough identified using an algorithm designed for administrative claims databases: A descriptive study.

Objective As population-based studies describing the characteristics of patients with refractory chronic cough (RCC) are sparse, the objective of this descriptive study was to identify and describe such patients using an algorithm developed for administrative claims databases and requiring validation in future. Methods We identified adults with chronic cough (N = 782,121) from Optum Clinformatics™ Data Mart as individuals with a 'cough event' (primary cough event; based on ICD codes/relevant prescriptions) and ≥2 cough events in the 56-180 preceding days. We applied several exclusion criteria to identify potential RCC cases and stratified them into probable, possible, and unlikely RCC cohorts by the number of cough events during 1-year follow up (≥3, 1-2 or 0 events, respectively). Patient characteristics were described during the year before the primary cough event and follow up. Results 16.8% (n = 131,772) of patients with chronic cough were potential RCC cases: 25.8% probable, 35.9% possible and 38.3% unlikely. The majority were female (66.4-70.5%); median age was 53-60 years. The most common comorbidities and cough-associated complications at baseline were: allergic rhinitis (30.7-39.1%), hypertension (37.3-47.7%), gastro-oesophageal reflux disease (23.7-34.3%), asthma (18.1-27.3%), insomnia (6.3-8.3%) and stress incontinence (2.5-3.9%). Among probable RCC cases, use of several medications was higher during follow up versus baseline: 52.7% versus 49.0% (cough treatments), 73.3% versus 69.0% (respiratory drugs), 40.5% versus 34.2% (gastrointestinal drugs) and 58.8% versus 56.1% (psychotherapeutics). Conclusion Our algorithm requires validation but provides a starting point to identify patients with RCC in claims databases in future studies.

Challenges and lessons learned from a long-term postauthorisation safety study programme of rivaroxaban in Europe.

OBJECTIVES: To describe opportunities and challenges experienced from the four pharmacoepidemiological database studies included in the rivaroxaban post authorisation safety study (PASS) programme and propose ways to maximise the value of population-based observational research when addressing regulatory requirements. DESIGN: PASS programme of rivaroxaban carried out as part of the regulatory postapproval commitment to the European Medicines Agency. SETTING: Clinical practice in Germany, the Netherlands, Sweden and the UK (electronic health records)-undertaken by pharmacoepidemiology research teams using country-specific databases with different coding structures. PARTICIPANTS: 355 152 patients prescribed rivaroxaban and 338 199 patients prescribed vitamin K antagonists. RESULTS: Two major challenges that were encountered throughout the lengthy PASS programme were related to: (1) finalising country-tailored study designs before the extent of rivaroxaban uptake was known, and (2) new research questions that arose during the programme (eg, those relating to an evolving prescribing landscape). RECOMMENDATIONS: We advocate the following strategies to help address these major challenges (should they arise in any future PASS): conducting studies based on a common data model that enable the same analytical tools to be applied when using different databases; maintaining early, clear, continuous communication with the regulator (including discussing the potential benefit of studying drug use as a precursor to planning a safety study); consideration of adaptive designs whenever uncertainty exists and following an initial period of data collection; and setting milestones for the review of study objectives.

Persistence to rivaroxaban therapy for stroke prevention in clinical practice in Italy: Rationale and design of the RITMUS-AF prospective observational cohort study.

Background: Non-valvular atrial fibrillation (NVAF) is a cardiac rhythm disturbance that increases the risk of stroke and is highly prevalent in Europe and Italy, increasingly with advancing age. Oral anticoagulation is a key component of stroke prevention in patients with NVAF, yet withdrawal or interruption of anticoagulation may transiently increase the risk of embolic events. Treatment persistence to anticoagulation is an important metric but one that is not well studied in patients with NVAF in Italy. The RITMUS-AF study aims to evaluate the persistence with rivaroxaban treatment for stroke prevention in patients with NVAF in Italy. Methods: RITMUS-AF is a prospective, observational cohort study of patients with NVAF in hospital cardiology departments with a non-vitamin K antagonist oral anticoagulant surveillance program across all 20 regions of Italy. The study population comprises consecutively screened, consenting patients with NVAF naïve to and newly treated with rivaroxaban for stroke prevention in routine clinical practice. The target enrollment is 800 patients; each patient will be followed for a maximum duration of 24 months. The primary endpoint is the proportion of patients who discontinue rivaroxaban treatment. Secondary endpoints are reasons for rivaroxaban discontinuation, dose changes and reasons for changes, switches to alternative therapies and the reasons for these decisions, and self-reported adherence. Data analyses will be exploratory and descriptive. Conclusion: RITMUS-AF will help to address the limited data in Italian clinical practice on treatment persistence and reasons for drug interruptions in patients with NVAF on rivaroxaban.

The global epidemiology of upper and lower gastrointestinal bleeding in general population: A systematic review.

BACKGROUND: Gastrointestinal bleeding (GIB) is a common and potentially life-threatening clinical event. To date, the literature on the long-term global epidemiology of GIB has not been systematically reviewed. AIM: To systematically review the published literature on the worldwide epidemiology of upper and lower GIB. METHODS: EMBASE® and MEDLINE were queried from 01 January 1965 to September 17, 2019 to identify population-based studies reporting incidence, mortality, or case-fatality rates of upper GIB (UGIB) or lower GIB (LGIB) in the general adult population, worldwide. Relevant outcome data were extracted and summarized (including data on rebleeding following initial occurrence of GIB when available). All included studies were assessed for risk of bias based upon reporting guidelines. RESULTS: Of 4203 retrieved database hits, 41 studies were included, comprising a total of around 4.1 million patients with GIB worldwide from 1980-2012. Thirty-three studies reported rates for UGIB, four for LGIB, and four presented data on both. Incidence rates ranged from 15.0 to 172.0/100000 person-years for UGIB, and from 20.5 to 87.0/100000 person-years for LGIB. Thirteen studies reported on temporal trends, generally showing an overall decline in UGIB incidence over time, although a slight increase between 2003 and 2005 followed by a decline was shown in 5/13 studies. GIB-related mortality data were available from six studies for UGIB, with rates ranging from 0.9 to 9.8/100000 person-years, and from three studies for LGIB, with rates ranging from 0.8 to 3.5/100000 person-years. Case-fatality rate ranged from 0.7% to 4.8% for UGIB and 0.5% to 8.0% for LGIB. Rates of rebleeding ranged from 7.3% to 32.5% for UGIB and from 6.7% to 13.5% for LGIB. Two main areas of potential bias were the differences in the operational GIB definition used and inadequate information on how missing data were handled. CONCLUSION: Wide variation was seen in estimates of GIB epidemiology, likely due to high heterogeneity between studies however, UGIB showed a decreasing trend over the years. Epidemiological data were more widely available for UGIB than for LGIB.

Long-Term Adherence and Persistence to Low-Dose Aspirin for the Prevention of Cardiovascular Disease: A Population-Based Cohort Study.

Methods: Using information from electronic health records in Germany and the United Kingdom (UK) in a common data model, we followed adults with ≥2 low-dose aspirin prescriptions (75-100 mg) during 2007-2018 for up to 10 years. Included individuals had no low-dose aspirin prescriptions in the year before the follow-up started (date of first low-dose aspirin prescription) and ≥12 months' observation. Adherence was determined using the medication possession ratio (MPR), and persistence was defined as continuous treatment disregarding gaps between prescriptions of <60 days; analyses were undertaken according to indication (primary/secondary CVD prevention). Results: We identified 144,717 low-dose aspirin users from Germany and 190,907 from the UK. Among patients with 5-10 years' follow-up, median adherence among secondary CVD prevention users was 60% in Germany and 75% in the UK. Among primary prevention users, median adherence was 50% for both countries. Persistence among secondary CVD prevention users was 58.3% at 2 years, 47.0% at 5 years, 35.2% at 10 years (Germany), and 67.5% at 2 years, 58.0% at 5 years, and 46.8% at 10 years (UK). Among primary CVD prevention users, persistence was 52.8% at 2 years, 41.6% at 5 years, 32.1% at 10 years (Germany), 56.3% at 2 years, 45.4% at 5 years, and 33.8% at 10 years (UK). Conclusions: Long-term adherence and persistence to low-dose aspirin are suboptimal; efforts for improvement could translate into a lower CVD burden in the general population.

Pulmonary thromboembolic events in COVID-19-A systematic literature review.

Pulmonary thromboembolic events have been linked to coronavirus disease 2019 (COVID-19), but their incidence and long-term sequelae remain unclear. We performed a systematic literature review to investigate the incidence of pulmonary embolism (PE), microthrombi, thrombosis in situ (thromboinflammatory disease), and chronic thromboembolic pulmonary hypertension (CTEPH) during and after COVID-19. PubMed and the World Health Organization Global Research Database were searched on May 7, 2021. Hospital cohort and database studies reporting data for ≥1000 patients and autopsy studies reporting data for ≥20 patients were included. Results were summarized descriptively. We screened 1438 records and included 41 references (32 hospital/database studies and 9 autopsy studies). The hospital/database studies reported the incidence of PE but not CTEPH, microthrombi, or thromboinflammatory disease. PE incidence varied widely (0%-1.1% of outpatients, 0.9%-8.2% of hospitalized patients, and 1.8%-18.9% of patients in intensive care). One study reported PE events occurring within 45 days after hospital discharge (incidence in discharged patients: 0.2%). Segmental arteries were generally the most common location for PE. In autopsy studies, PE, thromboinflammatory disease, and microthrombi were reported in 6%-23%, 43%-100%, and 45%-84% of deceased patients, respectively. Overall, the included studies mostly focused on PE during the acute phase of COVID-19. The results demonstrate the challenges of identifying and characterizing vascular abnormalities using current protocols (e.g., visual computed tomography reads). Further research is needed to detect subtle pulmonary vascular abnormalities, distinguish thromboinflammatory disease from PE, optimize treatment, and assess the incidence of long-term sequelae after COVID-19.

Risk factors for major gastrointestinal bleeding in the general population in Finland.

BACKGROUND: Data on non-drug related risk-factors for gastrointestinal bleeding (GIB) in the general population are limited, especially for life-style factors, clinical measurements and laboratory parameters. AIM: To identify and investigate non-drug risk factors for major GIB in the general population of Finland. METHODS: We performed a retrospective cohort study using data from the FINRISK health examination surveys, which have been conducted every 5 years across Finland from 1987 to 2007. Participants were adults aged 25 years to 74 years, excluding those with a previous hospitalization for GIB. Follow-up from enrollment was performed through linkage to national electronic health registers and ended at an event of GIB that led to hospitalization/death, death due to any other cause, or after 10 years. Covariates included demographics, socioeconomic and lifestyle factors, clinical measurements, laboratory parameters and comorbidities. Variable selection was undertaken using Least Absolute Shrinkage and Selection Operator (LASSO) and factors associated with GIB were identified using Cox regression. RESULTS: Among 33,508 participants, 403 (1.2%) experienced GIB [256 men (63.5%); mean age, 56.0 years (standard deviation (SD) ± 12.1)] and 33105 who did not experience GIB [15768 men (47.6%); mean age, 46.8 (SD ± 13) years], within 10 years of follow-up. Factors associated with a significantly increased risk of GIB were baseline age [per 10-year increase; hazard ratio (HR) 1.62, 95% confidence interval (CI): 1.42-1.86], unemployment (HR: 1.70, 95%CI: 1.11-2.59), body mass index (BMI) (HR: 1.15, 95%CI: 1.01-1.32), gamma-glutamyl transferase (GGT) (HR: 1.05, 95%CI: 1.02-1.09), precursors of GIB (HR: 1.90, 95%CI: 1.37-2.63), cancer (HR: 1.47, 95%CI: 1.10-1.97), psychiatric disorders (HR: 1.32, 95%CI: 1.01-1.71), heart failure (HR: 1.46, 95%CI: 1.04-2.05), and liver disorders (HR: 3.20, 95%CI: 2.06-4.97). Factors associated with a significantly decreased risk of GIB were systolic blood pressure (SBP) (HR: 0.78, 95%CI: 0.64-0.96), 6-10 cups of coffee a day (HR: 0.67, 95%CI: 0.46-0.99), or > 10 cups (HR: 0.43, 95%CI: 0.23-0.81). CONCLUSION: Our study confirms established risk-factors for GIB and identifies potential risk-factors not previously reported such as unemployment, BMI, GGT, SBP and coffee consumption.

Safety and effectiveness of appropriately and inappropriately dosed rivaroxaban or apixaban versus warfarin in patients with atrial fibrillation: a cohort study with nested case-control analyses from UK primary care.

OBJECTIVES: To investigate effects of appropriately and inappropriately dosed apixaban/rivaroxaban versus warfarin on effectiveness and safety outcomes in patients with non-valvular atrial fibrillation (NVAF). DESIGN: Cohort study with nested case-control analyses using primary care electronic health records (IQVIA Medical Research Data UK database). SETTING: UK primary care. PARTICIPANTS: Patients aged ≥18 years with NVAF newly prescribed apixaban (N=14 701), rivaroxaban (N=14 288) or warfarin (N=16 175) between 1 January 2012 and 30 June 2018, and followed up to 31 December 2018. PRIMARY AND SECONDARY OUTCOME MEASURES: Incident cases of ischaemic stroke/systemic embolism (IS/SE) and intracranial bleeding (ICB). Cases were matched to controls on age, sex and OAC naïve status. Using logistic regression, adjusted ORs with 95% CIs were calculated for the outcomes comparing apixaban/rivaroxaban use (appropriate or inappropriate dosing based on the product label criteria) and warfarin. RESULTS: For IS/SE, ORs (95% CIs) for apixaban versus warfarin were 1.19 (0.92-1.52) for appropriate dose and 1.01 (0.67-1.51) for inappropriate dose; for rivaroxaban versus warfarin, estimates were 1.07 (0.83-1.37) for appropriate dose and 1.21 (0.78-1.88) for inappropriate dose. For ICB, ORs (95% CIs) for apixaban versus warfarin were 0.67 (0.44-1.00) for appropriate dose and 0.45 (0.21-0.95) for inappropriate dose; for rivaroxaban versus warfarin, estimates were 0.81 (0.55-1.20) for appropriate dose and 1.14 (0.56-2.31) for inappropriate dose. CONCLUSIONS: Dosing appropriateness in NVAF was not associated with a significant difference in IS/SE risk or increase in ICB risk versus warfarin. These findings may reflect residual confounding and biases that were difficult to control, as also seen in other observational studies. They should, therefore, be interpreted with caution, and prescribers should adhere to the dosing instructions in the respective Summary of Product Characteristics. Further studies on this topic from real-world populations are needed.

Time Trends and Treatment Pathways in Prescribing Individual Oral Anticoagulants in Patients with Nonvalvular Atrial Fibrillation: An Observational Study of More than Three Million Patients from Europe and the United States.

Background: Data directly comparing trends in the use of different oral anticoagulants (OACs) among patients with atrial fibrillation (AF) from different countries are limited. We addressed this using a large-scale network cohort study in the United States (US), Belgium, France, Germany, and the United Kingdom (UK). Methods: We used nine databases (claims or electronic health records) that had been converted into the Observational Medical Outcomes Partnership Common Data Model with analysis performed using open-source analytical tools. We identified adults with AF and a first OAC prescription, either vitamin K antagonist (VKA) or direct oral anticoagulant (DOAC), from 2010 to 2017. We described time trends in use, continuation, and switching. Results: In 2010, 87.5%-99.8% of patients started on a VKA. By 2017, the majority started on a DOAC: 87.0% (US), 88.3% (Belgium), 93.1% (France), 88.4% (Germany), and 86.1%-86.7% (UK). In the UK, DOACs became the most common starting OAC in 2015, 2-3 years later than elsewhere. Apixaban was the most common starting OAC by 2017, 50.2%-57.8% (US), 31.4% (Belgium), 45.9% (France), 39.5% (Germany), and 49.8%-50.5% (UK), followed by rivaroxaban, 24.8%-32.5% (US), 25.7% (Belgium), 38.4% (France), 24.9% (Germany), and 30.2%-31.2% (UK). Long-term treatment was less common in the US than in Europe, especially the UK. A minority of patients switched from their index OAC in the short and long term. Conclusions: From 2010 to 2017, VKA use had significantly declined and DOAC use had significantly increased in the US and Europe. Apixaban was the most prescribed OAC in 2017, followed by rivaroxaban.

Safety and effectiveness of low-dose aspirin for the prevention of gastrointestinal cancer in adults without atherosclerotic cardiovascular disease: a population-based cohort study.

OBJECTIVE: To assess the association between low-dose aspirin and the incidence of colorectal cancer (CRC), gastric cancer (GC), oesophageal cancer (EC) and gastrointestinal bleeding (GIB) in adults without established atherosclerotic cardiovascular disease. DESIGN: Cohort study with propensity score matching of new-users of aspirin to non-users. SETTING: Clinical Data Analysis and Reporting System database, Hong Kong. PARTICIPANTS: Adults ≥40 years with a prescription start date of either low-dose aspirin (75-300 mg/daily) or paracetamol (non-aspirin users) between 1 January 2004 to 31 December 2008 without a history of atherosclerotic cardiovascular disease. MAIN OUTCOME MEASURES: The primary outcome was the first diagnosis of gastrointestinal cancer (either CRC, GC or EC) and the secondary outcome was GIB. Individuals were followed from index date of prescription until the earliest occurrence of an outcome of interest, an incident diagnosis of any type of cancer besides the outcome, death or until 31 December 2017. A competing risk survival analysis was used to estimate HRs and 95% CIs with death as the competing risk. RESULTS: After matching, 49 679 aspirin and non-aspirin users were included. The median (IQR) follow-up was 10.0 (6.4) years. HRs for low-dose aspirin compared with non-aspirin users were 0.83 for CRC (95% CI, 0.76 to 0.91), 0.77 for GC (95% CI, 0.65 to 0.92) and 0.88 for EC (95% CI, 0.67 to 1.16). Patients prescribed low-dose aspirin had an increased risk of GIB (HR 1.15, 95% CI, 1.11 to 1.20), except for patients prescribed proton pump inhibitors or histamine H2-receptor antagonists (HR 1.03, 95% CI, 0.96 to 1.10). CONCLUSION: In this cohort study of Chinese adults, patients prescribed low-dose aspirin had reduced risks of CRC and GC and an increased risk of GIB. Among the subgroup of patients prescribed gastroprotective agents at baseline, however, the association with GIB was attenuated.

Trends in the use of oral anticoagulants, antiplatelets and statins in four European countries: a population-based study.

PURPOSE: To evaluate time trends in the prevalence of antithrombotic and statin use in four European countries. METHODS: Using population-based data from the United Kingdom, Denmark, Spain and Italy between 2010 and 2018, we calculated standardized annual prevalence proportions of antithrombotics and statin use, and changes in prevalence proportions (2018 vs. 2010). RESULTS: Prevalence proportion of statins increased from 24.8% to 24.6% (UK), 21.0% to 22.3% (Region of Southern Denmark [RSD]), 12.9% to 14.3% (Udine, Italy), and 20.3% to 23.2% (Spain). Prevalence proportions of antithrombotics declined in all four countries: 18.7% to 15.9% (UK; - 2.8% points), 18.9% to 18.1% (RSD; - 0.8% points), 17.7% to 16.6% (Udine; - 1.1% points) and 15.0% to 13.6% (Spain; - 1.4% points). These declines were driven by reductions in low-dose aspirin use: 15.3% to 8.9% (UK; - 6.4% points), 16.3% to 9.5% (RSD; - 6.8% points), 13.5% to 11.6% (Udine; - 1.9% points), and 10.2% to 8.8% (Spain; - 1.4% points). In the UK, low-dose aspirin use declined from 9.1% to 4.3% (- 4.8% points) for primary CVD prevention, and from 49.6% to 36.9% (- 12.7% points) for secondary prevention. Oral anticoagulant use gradually increased but did not fully account for the decrease in low-dose aspirin use. CONCLUSIONS: Antithrombotic use in the UK, RSD, Udine and Spain declined between 2010 and 2018, driven by a reduction in use of low-dose aspirin that is not completely explained by a gradual increase in OAC use. Use of statins remained constant in the UK, and increased gradually in the RSD, Udine and Spain.

Public health impact of low-dose aspirin on colorectal cancer, cardiovascular disease and safety in the UK - Results from micro-simulation model.

BACKGROUND: Low-dose aspirin therapy reduces the risk of cardiovascular disease and may have a positive effect on the prevention of colorectal cancer. We evaluated the population-level expected effect of regular low-dose aspirin use on cardiovascular disease (CVD), colorectal cancer (CRC), gastrointestinal bleeding, symptomatic peptic ulcers, and intracranial hemorrhage, using a microsimulation study design. METHODS: We used individual-level state transition modeling to assess the impact of aspirin in populations aged 50-59 or 60-69 years old indicated for low-dose aspirin usage for primary or secondary CVD prevention. Model parameters were based on data from governmental agencies from the UK or recent publications. RESULTS: In the 50-59 years cohort, a decrease in incidence rates (IRs per 100 000 person years) of non-fatal CVD (-203 and -794) and fatal CVD (-97 and-381) was reported in the primary and secondary CVD prevention setting, respectively. The IR reduction of CRC (-96 and -93) was similar for primary and secondary CVD prevention. The IR increase of non-fatal (116 and 119) and fatal safety events (6 and 6) was similar for primary and secondary CVD prevention. Similar results were obtained for the 60-69 years cohort. CONCLUSIONS: The decrease in fatal CVD and CRC events was larger than the increase in fatal safety events and this difference was more pronounced when low-dose aspirin was used for secondary compared to primary CVD prevention. These results provide a comprehensive image of the expected effect of regular low-dose aspirin therapy in a UK population indicated to use aspirin for CVD prevention.

Patient Preferences of Low-Dose Aspirin for Cardiovascular Disease and Colorectal Cancer Prevention in Italy: A Latent Class Analysis.

BACKGROUND: Patients taking low-dose aspirin to prevent cardiovascular disease (CVD) may also benefit from a reduced risk of colorectal cancer (CRC). OBJECTIVE: The aim was to examine the preferences of people eligible for preventive treatment with low-dose aspirin and the trade-offs they are willing to make between CVD prevention, CRC prevention, and treatment risks. METHODS: A cross-sectional study using a discrete choice experiment (DCE) survey was conducted in Italy in 2019 to elicit preferences for three benefit attributes (prevention of ischemic stroke, myocardial infarction, and CRC) and four risk attributes (intracranial and gastrointestinal bleeding, peptic ulcer, and severe allergic reaction) associated with use of low-dose aspirin. Latent class logit models were used to evaluate variation in treatment preferences. RESULTS: The DCE survey was completed by 1005 participants eligible for use of low-dose aspirin. A four-class model had the best fit for the primary CVD prevention group (n = 491), and a three-class model had the best fit for the secondary CVD prevention group (n = 514). For the primary CVD prevention group, where classes differed on age, education level, type 2 diabetes, exercise, and low-dose aspirin use, the most important attributes were intracranial bleeding (two classes), myocardial infarction (one class), and CRC (one class). For the secondary CVD prevention group, where classes differed on various comorbidities, self-reported health, exercise, and CVD medication use, the most important attributes were intracranial bleeding (two classes), myocardial infarction (one class), and gastrointestinal bleeding (one class). CONCLUSION: Patient preferences for the benefits and risks of low-dose aspirin differ significantly among people eligible for treatment as primary or secondary CVD prevention.

Validation of venous thromboembolism diagnoses in patients receiving rivaroxaban or warfarin in The Health Improvement Network.

PURPOSE: To describe the effect that validation of venous thromboembolism (VTE) coded entries in the health improvement network (THIN) has on incidence rates of VTE among a cohort of rivaroxaban/warfarin users. METHODS: Among 36 701 individuals with a first prescription for rivaroxaban/warfarin between 2012 and 2015, we performed a two-step VTE case identification process followed by a two-step case validation process involving manual review of patient records. A valid case required a coded entry for VTE at some point after their first rivaroxaban/warfarin prescription with evidence of referral/hospitalization either as a coded entry or entered as free text. Positive predictive values (PPVs) with 95% confidence intervals (CIs) were calculated using validated cases as the gold standard. Incidence rates were calculated per 1000 person-years with 95% CIs. RESULTS: We identified 2166 patients with a coded entry of VTE after their initial rivaroxaban/warfarin prescription; incidence rate of 45.31 per 1000 person-years (95% CI: 43.49-47.22). After manual review of patient records including the free text, there were 712 incident VTE cases; incidence rate of 14.90 per 1000 person-years (95% CI: 13.85-16.02). The PPV for coded entries of VTE alone was 32.9%, and the PPV for coded entries of VTE with a coded entry of referral/hospitalization was 39.8%; this increased to 69.6% after manual review of coded clinical entries in patient records. CONCLUSIONS: Among rivaroxaban/warfarin users in THIN, valid VTE case identification requires manual review of patient records including the free text to prevent outcome misclassification and substantial overestimation of VTE incidence rates.

Discontinuation of oral anticoagulation in atrial fibrillation and risk of ischaemic stroke.

OBJECTIVE: To evaluate associations between oral anticoagulant (OAC) discontinuation and risk of ischaemic stroke (IS) among patients with atrial fibrillation (AF). METHODS: We undertook a population-based cohort study with nested case-control analysis using UK primary care electronic health records (IQVIA Medical Research Data-UK) and linked registries from the Region of Southern Denmark (RSD). Patients with AF (76 882 UK, 41 526 RSD) were followed to identify incident IS cases during 2016-2018. Incident IS cases were matched by age and sex to controls. Adjusted ORs for OAC discontinuation (vs current OAC use) were calculated using logistic regression. RESULTS: We identified 616 incident IS cases in the UK and 643 in the RSD. ORs for IS with any OAC discontinuation were 2.99 (95% CI 2.31 to 3.86, UK) and 2.30 (95% CI 1.79 to 2.95, RSD), for vitamin K antagonist discontinuation they were 2.38 (95% CI 1.72 to 3.30, UK) and 1.83 (95% CI 1.34 to 2.49, RSD), and for non-vitamin K antagonist oral anticoagulant discontinuation they were 4.59 (95% CI 2.97 to 7.08, UK) and 3.37 (95% CI 2.35 to 4.85, RSD). ORs were unaffected by time since discontinuation and duration of use. Annually, up to 987 IS cases in the UK and 132 in Denmark could be preventable if OAC therapy is not discontinued. CONCLUSIONS: Our results suggest that patients with AF who discontinue OAC therapy have a significant twofold to threefold higher risk of IS compared with those who continue therapy. Addressing OAC discontinuation could potentially result in a significant reduction in AF-attributed IS.

Association Between Low-Dose Aspirin Use and Colorectal Cancer Incidence in Taiwan.

Importance: Population-based East Asian data have corroborated reports from non-Asian settings on the association between low-dose aspirin and a lower risk of colorectal cancer (CRC). Objective: To evaluate the association between duration and recency of low-dose aspirin use and CRC risk. Design, Setting, and Participants: This nested case-control study included individuals who initiated aspirin use and matched individuals who did not use aspirin. Data were collected from Taiwan National Health Insurance and Taiwan Cancer Registry from 2000 through 2015. CRC cases were age- and sex-matched in a 1:4 ratio with individuals in a control group, identified from a cohort of individuals who used and did not use aspirin through risk-set sampling. Data analysis was conducted from June 2018 to July 2019. Exposures: Low-dose aspirin use was defined as receiving less than 150 mg per day, whereas 100 mg/d was most commonly used. Based on duration and recency of low-dose aspirin use between cohort entry (initiation date of low-dose aspirin for aspirin use group or randomly assigned date for those who did not use aspirin) and index date (CRC diagnosis date for individuals in the case group and the diagnosis date for the 4 corresponding matched individuals in the control group), the 3 following mutually exclusive exposure groups served as the basis for analysis: (1) long-term current low-dose aspirin use, (2) episodic low-dose aspirin use, and (3) no low-dose aspirin use (the reference group). Main Outcomes and Measures: CRC risk among the 3 exposure groups. Results: Among 4 710 504 individuals (2 747 830 [51.7%] men; median [interquartile range] age at cohort entry in initiator group, 61 [52-71] years; median [interquartile range] age at cohort entry in nonuse group, 59 [51-68] years), 79 095 CRC cases (1.7% of study cohort) were identified. Compared with no low-dose aspirin use, the adjusted odds ratio (OR) for long-term current low-dose aspirin use and CRC risk was 0.89 (95% CI, 0.85-0.93); for episodic use, 0.88 (95% CI, 0.86-0.89). Adjusted ORs of 0.69 (95% CI, 0.63-0.76) and 0.64 (95% CI, 0.61-0.67) were observed for long-term current use and episodic low-dose aspirin use within the subcohort of individuals who initiated low-dose aspirin between age 40 and 59 years. Conclusions and Relevance: In this study, low-dose aspirin use was associated with 11% lower CRC risk in an East Asian population, and this association was larger when low-dose aspirin use started before age 60 years.

Thirty-Year Incidence and Mortality Trends in Upper and Lower Gastrointestinal Bleeding in Finland.

Importance: Epidemiological data on lower gastrointestinal bleeding (GIB) in the general population are sparse. Objective: To describe the incidence, recurrence, mortality, and case fatality rates of major upper GIB and lower GIB in the general population of Finland between 1987 and 2016. Design, Setting, and Participants: This prospective cohort study used data from the 1987 to the 2012 cycles of the National FINRISK Study, a health examination survey that was conducted every 5 years in Finland. Survey participants were adults aged 25 to 74 years who were recruited from a population register by random sampling; those with a history of hospitalization for GIB were excluded. Participants were followed up from survey enrollment to onset of GIB that led to hospitalization, death from any cause, or study end (December 31, 2016). Follow-up was performed through linkage with national electronic health registers. Data were analyzed from February 1, 2019, to January 31, 2020. Main Outcomes and Measures: Incidence, recurrence, mortality, and case fatality rates for all, upper, lower, and unspecified GIB. Outcome measures were stratified by sex and age group. Results: Among the 39 054 participants included in the study, 494 (1.3%) experienced upper GIB (321 men [65.0%]; mean [SD] age, 52.8 [12.1] years) and 645 (1.7%) had lower GIB (371 men [57.5%]; mean [SD] age, 54.0 [11.7] years). The age-standardized incidence rate was 0.94 per 1000 person-years (95% CI, 0.85-1.04) for upper GIB and 1.26 per 1000 person-years (95% CI, 1.15-1.38) for lower GIB; the incidence was higher in men than in women. Between 1987 and 2016 the incidence rate of upper GIB remained mostly stable, ranging from 0.40 to 0.66 per 1000 person-years, whereas constant increases occurred in the incidence of lower GIB until the rate stabilized. The proportion of recurrent GIB events showed an increasing trend from 1987 to 2016. The upper GIB-specific mortality was higher (0.07 per 1000 person-years; 95% CI, 0.04-0.09) than the lower GIB-specific mortality (0.01 per 1000 person-years; 95% CI, 0.001-0.03). Case fatality was high for those with upper GIB (7.0%; 95% CI, 4.7-10.1) compared with those with lower GIB (0.4%; 95% CI, 0.1-1.3). Case fatality remained stable over the years but was higher in men (between 5% and 10%) than women (<2%) with GIB. Conclusions and Relevance: This study found that the overall incidence rate of upper GIB was lower than the incidence of lower GIB, but the recurrence, mortality, and 28-day case fatality were higher in participants with upper GIB. These data can serve as a reference when putting into context the rates of drug-associated GIB and can inform efforts to improve GIB care and outcome and to prevent rebleeding or death for patients with major GIB.

Bleeding associated with low-dose aspirin: Comparison of data from the COMPASS randomized controlled trial and routine clinical practice.

Randomized controlled trials (RCTs) have strong internal validity but often have limited external validity. Observational studies have good generalizability and an increasing role in key healthcare decision making. We compared incidence rates of intracranial and major gastrointestinal bleeds in the low-dose aspirin arm (N = 9126) of the COMPASS double-blind RCT (conducted at 602 centres in 33 countries) with those from an observational cohort of preventative low-dose aspirin users (N = 54,140) in a primary care database representative of the UK general population - The IQVIA Medical Research Data UK (IMRD-UK). In our observational study analysis, we restricted follow-up to 2 years to be comparable with the duration of the COMPASS trial. Among low-dose aspirin users, incidence rates per 1000 person-years (95% confidence intervals [CIs]) in the IMRD-UK cohort and COMPASS trial participants, respectively, were 0.6 (0.5-0.8) vs. 1.4 (0.9-2.1) for intracranial bleeds, and 3.5 (3.1-3.8) vs. 3.7 (2.9-4.8) for major gastrointestinal bleeds. These broadly comparable bleeding rates among COMPASS trial participants and an observational cohort of low-dose aspirin users in IMRD-UK support the use of the latter for generating robust therapeutic evidence, and indicate that the rates from the COMPASS trial are broadly consistent with realistic population-based rates.

Rationale and design of a European epidemiological post-authorization safety study (PASS) program: rivaroxaban use in routine clinical practice.

BACKGROUND: Rivaroxaban is a highly selective factor Xa inhibitor approved for use in Europe for multiple indications. STUDY DESIGN AND METHODS: The European rivaroxaban epidemiological post-authorization safety study (PASS) program consists of seven complementary observational studies. For four of the studies, data are obtained from health-care databases in the UK, the Netherlands, Germany, and Sweden. These database studies describe patterns of rivaroxaban use and patient characteristics over time, and investigate safety and effectiveness outcomes in new users of rivaroxaban using a cohort analysis and nested case-control analysis. To put these results in context, safety outcomes are also analyzed in new users of standard of care. In addition, a modified prescription event monitoring study conducted in the early post-launch phase in primary care, and two specialist cohort event monitoring studies that investigated rivaroxaban use in the secondary care hospital setting, systematically collected drug utilization and safety data via questionnaires completed by health-care professionals in the UK. DISCUSSION: The European rivaroxaban epidemiological PASS is a comprehensive program of complementary studies generating evidence from patients treated in routine clinical practice that will expand our understanding of the risk-benefit profile of rivaroxaban.

Low-dose aspirin and risk of gastric and oesophageal cancer: A population-based study in the United Kingdom using The Health Improvement Network.

There is increasing interest regarding potential protective effects of low-dose aspirin against various gastrointestinal cancers. We aimed to quantify the association between use of low-dose aspirin and risk of gastric/oesophageal cancer using a population-based primary care database in the UK. Between January 2005 and December 2015, we identified a cohort of 223 640 new users of low-dose aspirin (75-300 mg/day) and a matched cohort of nonusers at the start of follow-up from The Health Improvement Network. Cohorts were followed to identify incident cases of gastric/oesophageal cancer. Nested case-control analyses were conducted and adjusted odds ratios (ORs) with 95% confidence intervals (CIs) were calculated for current vs nonuse of low-dose aspirin using logistic regression. Current use was defined as when low-dose aspirin lasted 0 to 90 days before the index date (event date for cases, random date for controls) and previous duration was ≥1 year. We identified 727 incident cases of gastric cancer and 1394 incident cases of oesophageal cancer. ORs (95% CIs) were 0.46 (0.38-0.57) for gastric cancer and 0.59 (0.51-0.69) for oesophageal cancer. The effect remained consistent with no clear change seen between previous duration of low-dose aspirin use of 1-3, 3-5 or >5 years. The reduced risks was seen with 75 mg/day, and effects were consistent in lag-time analyses. In conclusion, our results indicate that use of low-dose aspirin is associated with a 54% reduced risk of gastric cancer and a 41% reduced risk of oesophageal cancer as supported by mechanistic data.